Although cocaine addiction is a major public health problem, currently no effective pharmacological treatment options exist. With relapse rates estimated at around 40-60%, developing a better understanding of the mechanisms underlying relapse could provide us with the means to develop better treatment options. Stress has been shown to elicit relapse to cocaine seeking in human addicts and reinstatement of drug seeking in animals models; however, the molecular mechanisms by which stress leads to relapse is unknown. Recent work in our lab has demonstrated that cAMP response element binding protein (CREB) is necessary for stress- but not cocaine-induced reinstatement of conditioned place preference using mice with a constitutive deletion of CREB. Currently, it is unclear which aspects of the neural circuitry depend on CREB to drive stress-induced reinstatement of cocaine seeking. Utilizing behavioral, immunohistochemical, and neuropharmacological approaches, this grant aims to examine the role of CREB in stress-induced reinstatement of cocaine conditioned place preference. Initially, we will examine the role of behavioral coping strategies in response to stress will be examined by examining the ability of stressors that do not engage altered behavioral responding in CREB deficient mice to lead to resinstatement of conditioned reward. Additionally, we will examine differences between both naive and cocaine-experienced wildtype and CREB deficient mice in the ability of stress to engage neurobiological circuitry implicated in stress-induced reinstatement. Finally, interactions between CREB and corticotropin-releasing factor (CRF) will be elucidated by local infusions of CRF into the bed nucleus of the stria terminalis (BNST) and the ventral tegmental area (VTA) prior to reinstatement. The goal of this research is to gain a better understanding of how stressful experiences can lead to drug relapse. By investigating the role of CREB in both the behavioral responses to stress as well as the molecular mechanisms underlying the interactions between stress and drug seeking we can identify new therapeutic targets for drug discovery